We describe plans for a randomized controlled clinical trial to determine the effects of omega-3 fatty acid supplementation on urine protein excretion in adults with diabetes and kidney disease defined by the presence proteinuria. Diabetes is the most common cause of end-stage-kidney disease in the United States. Primary approaches to prevent or slow the progression of diabetic kidney disease include lifestyles changes and pharmacological therapy aimed at achieving and maintaining glucose, blood pressure and cholesterol goals. Advances in our understanding of the pathogenesis of diabetic kidney disease have laid the foundation for testing novel therapies, such as omega-3 fatty acid supplements, that affect underlying mechanisms of the disease such as inflammation, oxidative stress and endothelial dysfunction. We will conduct a single center randomized trial to test the effectiveness of daily supplementation of omega-3 fatty acids (0, 0.9 or 3.6 g DHA/EPA) over 3 months in 30 adults with diabetes and proteinuria, on urine protein excretion. Participants will be randomized in a crossover trial to four daily capsules of omega-3 fatty acid supplements or to identical appearing placebos (corn oil). Each participant will receive either a daily dose of 0, 0.9 or 3.6 g/day EPA+DHA . Urine protein excretion, measured by several techniques will be the primary outcome variable. The association between change in urine protein excretion with change in eGFR, blood pressure, markers of oxidation and inflammation, and change in urine protein excretion patterns will be explored and related to the intervention. The proposed study is ideally suited for the R21 funding mechanism. First, it is adequately powered to allow us to determine significant changes in urine protein excretion as a result of the intervention. Secondly, we measure explanatory variables reflective of the underlying glomerular and tubulointerstitial pathophysiology. Finally, understanding the short-term effects of omega-3 fatty acid supplementation on markers of kidney damage and function is a necessary first step in providing the justification for a large scale clinical trial with clinically meaningful endpoints (next step). PUBLIC HEALTH RELEVANCE: In this application we describe plans for a randomized placebo-controlled clinical trial to test the benefits of daily omega-3 fatty acids (fish oils) supplements at reducing urine protein excretion and other biomarkers of kidney injury in adults with diabetes and evidence for kidney disease. Participants will be randomize to receive 0, 0.9, and 3.6 grams per day of omega-3 fatty acids (fish oils) or placebo (corn oil) each day for three 6 week periods in a cross-over study design. We are hopeful that omega-3 fatty acid supplements may add to current therapies that help protect against progression of kidney disease, a common and devastating complication of diabetes.